1. Field of the Invention
The present invention relates generally to the field of molecular biology and medicine. More particularly, it concerns compounds for the treatment of cancer or inflammation.
2. Description of Related Art
Although a large portion of estrogen receptor (ER)-positive breast cancer can be prevented and treated with ER modulators (such as tamoxifen and raloxifene) and aromatase inhibitors (such as anastrozole and letrozole) as preventive and therapeutic drug, these available drugs fail to prevent or treat the rest ER-positive breast cancers (approximately 45% of all ER-positive) and all ER-negative breast cancers (both accounting for approximately 60% of all breast cancer cases, including triple-negative breast cancer). In particular, ER-negative breast cancer including triple negative breast cancer does not respond to hormonal therapy and incline to develop metastasis. Thus, effective targets and agents are urgently needed to prevent and treat the resistant ER-positive breast cancer and all ER-negative including triple negative breast cancers.
Signal Transducers and Activators of Transcription (STATs) are a family of transcription factors involved in the regulation of early embryonic development, the immune response, cell proliferation, differentiation, and apoptosis (Takeda et al. 1999; Takeda et al. 1998). Previous studies have shown that STAT1 regulates remodeling of the mammary gland during involution, STAT3 regulates lobuloalveolar apoptosis during involution, and STAT5 regulates lobuloalveolar proliferation, differentiation, and expansion in the normal mammary gland development (Chapman et al. 1999; Watson, 2001). Sufficient data also demonstrate that STATs play an important role in breast carcinogenesis (Yu et al. 2004). Particularly, STAT3 activation promotes growth and survival of mammary tumors by upregulating Bcl-xL, Bcl-2, and surviving. Stimulating epidermal growth factor receptor (EGFR), Src, and Jaks will activate STAT3 (Turkson 2004). Increased STAT3 transcriptional activity was found to correlate with ER-negative phenotype in breast cancer cell lines and in primary human invasive ductal breast carcinomas (Yeh et al. 2006). High levels of activated STAT3 are often found to correlate with poor prognosis in human breast cancer patients in terms of metastatic progression (Ranger et al. 2009). Therefore, STAT3 represents a promising target for the prevention and treatment of both ER-positive and ER-negative breast cancer and also other cancers such as pancreatic, head/neck, prostate and lung cancers. However, current strategies of inhibiting STAT3 activity by means of blocking peptides, blockade of translocation, disrupting dimerization, or modulating phosphatase activity have not sufficiently inhibit STAT3 activity in cancer cells.
Despite substantial effort in the design of both peptidic and non-peptidic inhibitors that target STAT3, only a limited number of STAT3 inhibitors have been developed into a clinical trial. While peptide-based inhibitors can bind to STAT3 with high affinities, they suffer from the lack of cellular permeability due to both their peptidic nature and the negative charges on the phosphotyrosine group. Non-peptidic small-molecule inhibitors are relatively more cell-permeable, but most of the reported compounds such as Stattic bind to STAT3 with weak affinities (IC50=5.1 μM) and the cellular activity cannot be clearly attributed to STAT3 targeting (Schust et al. 2006). Recently, niclosamide has been identified to potently inhibit the activation, nuclear translocation, and transactivation of STAT3 (IC50=0.25 μM) but have no obvious effects on the closely related STAT1 and STAT5 proteins, the upstream JAK1, JAK2, and Src kinases, or other receptor tyrosine kinases (Ren et al. 2010). Unfortunately, niclosamide does not have an ideal pharmacokinetic profile in humans as an anticestodal drug, displaying poor oral bioavailability. Thus, its clinical use as anticancer agent is limited because of its moderate potency, poor solubility, and poor bioavailability. Clearly, there is a need for new STAT3 inhibitors that could be further developed as clinical candidates for molecular mechanism-based apoptosis, such as the treatment of cancer.